N-((phenyl, benzodioxinyl or N-heteroarylpiperazinyl)alkyl)-N-(N-heteroaryl)substituted carboxamides

Abstract

Piperazine derivatives of formula I ##STR1## and their pharmaceutically acceptable acid addition salts are 5-HT 1A binding agents, particularly 5-HT 1A antagonists and may be used, for example, as anxiolytics. In the formula A is C 2-4 alkylene chain optionally substituted by lower alkyl, Z is oxygen or sulphur, R is hydrogen or lower alkyl, R 1 is a mono or bicyclic aryl or heteroaryl radical, R 2 is a mono or bicyclic heteroaryl radical and R 3 is hydrogen or a specified radical such as lower alkyl, cycloalkyl, aryl, heteroaryl or optionally substituted amino.

What is claimed is: 
     
       1. A compound of the formula ##STR13## or a pharmaceutically acceptable acid addition salt thereof, wherein A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups; Z is oxygen or sulphur;   R is hydrogen or lower alkyl;   R 1  is aryl, tetrahydronaphthyl, heteroaryl, wherein aryl is phenyl or naphthyl each of which may be optionally substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, halogen, haloloweralkyl, nitro, nitrile, aminocarbonyl, loweralkoxycarbonyl, amino, loweralkylamino, or di-loweralkylamino, and heteroaryl is a monocyclic aromatic heterocyclic ring having 5 ring members and having as heteroatoms one or two N atoms or one N atom and one O or S atom, or a monocyclic aromatic heterocyclic ring having 6 ring members and having as heteroatoms one or two N atoms, or a bicyclic aromatic heterocyclic ring system having one such 5 or 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, wherein such heteroaryl or tetrahydronaphthyl ring may be optionally substituted as for aryl,   or R 1  is a bicyclic oxygen-containing aryl radical of the formula ##STR14##  wherein the heterocyclic oxygen-containing ring has 5 to 7 ring members, said heterocyclic ring being non-aromatic and optionally having one further hetero ring member selected from --O--, --S--, --SO 2  or NR 7 , wherein R 7  is hydrogen or lower alkyl and wherein R 8  and R 9  represent hydrogen or one or more substituents independently selected from lower alkyl, halogen, hydroxy, loweralkoxy, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkanoyloxy(loweralkyl), loweralkylcarbonyl, loweralkylcarbonyl(loweralkyl), amino, loweralkylamino or di-loweralkylamino,   or R 1  is an bicyclic oxygen-containing aryl radical of the formula ##STR15##  wherein R 8  and R 9  are as defined above; R 2  is a monocyclic aromatic heterocyclic ring having 6 members and having as heteroatoms one or two N atoms or a bicyclic aromatic heterocyclic ring system having one such 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, which may be optionally substituted as for aryl, provided that, said bicyclic heterocyclic radical is connected to the amino nitrogen of formula I via such heterocyclic ring; and   R 3  is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(loweralkyl), aryl, aryl(loweralkyl), a group of formula --NR 4  R 5 , or a group of formula OR 6 , in which R 4  is hydrogen, lower alkyl, aryl or aryl(loweralkyl) and R 5  is hydrogen, lower alkyl, --CO(loweralkyl), aryl, --COaryl, aryl(loweralkyl), cycloalkyl or cycloalkyl(loweralkyl), or R 4  and R 5  together with the nitrogen atom to which they are both attached represent azetidino, pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino which may be optionally substituted by lower alkyl, aryl or aryl(loweralkyl), and R 6  is lower alkyl, cycloalkyl, cycloalkyl(loweralkyl), aryl, or aryl(loweralkyl),   wherein aryl is as defined for R 1  and cycloalkyl or cycloalkenyl is a mono-, bi-, tri-, or tetracyclic hydrocarbon group of 3 to 12 carbon atoms.   
     
     
       2. A compound as claimed in claim 1 in which A is --(CH 2 ) 2  --, --(CH 2 ) 3  --, --(CH 2 ) 4  -- or --CH(CH 3 ).CH 2  --. 
     
     
       3. A compound as claimed in claim 1 in which R is hydrogen. 
     
     
       4. A compound as claimed in claim 1 in which R 1  is o-methoxyphenyl, o-isopropylphenyl, 4-fluoro-2-methoxyphenyl, 2,3-dihydro[1,4]-benzodioxan-5-yl, pyrimid-2-yl, 1-naphthyl, 3-(1,2-benzisothiazolyl), 1-(7-methoxynaphthyl) or 1-(5,6,7,8-tetrahydro)naphthyl. 
     
     
       5. A compound as claimed in claim l in which R 2  is pyridyl-2-yl, quinolin-2-yl or thiazol-2-yl. 
     
     
       6. A compound as claimed in claim 1 in which R 3  is lower alkyl, cycloalkyl, cycloalkenyl, phenyl, piperidino or -NHcycloalkyl. 
     
     
       7. A compound as claimed in claim 1 which is N-(2-(1-(4-(2-methoxyphenyl)piperazinyl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       8. A compound as claimed in claim 1 which is N-cyclohexyl-N-(2-(1-(4-(2-methoxyphenyl)-piperazinyl))ethyl)-N-(2-pyridinyl)urea or a pharmaceutically acceptable salt thereof. 
     
     
       9. A compound as claimed in claim 1 which is N-(2-(1-(4-(2-methoxyphenyl)piperazinyl))ethyl)-N-(2-pyridinyl)benzamide or a pharmaceutically acceptable salt thereof. 
     
     
       10. A compound as claimed in claim 1 which is N-(2-(1-(4-(2-methoxyphenyl)piperazinyl))ethyl)-N-(2-pyridinyl)trimethylacetamide or a pharmaceutically acceptable salt thereof. 
     
     
       11. A compound as claimed in claim 1 which is N-(2-(1-(4-(2-methoxyphenyl)piperazinyl))ethyl)-N-(2-thiazolyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       12. A compound as claimed in claim 1 which is N-(2-(1-(4-(4-fluoro-2-methoxyphenyl)piperazinyl))-ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       13. A compound as claimed in claim 1 which is N-(2-(1-(4-(2,3-dihydro-1,4-benzodioxin-5-yl)-piperazinyl))ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       14. A compound as claimed in claim 1 which is N-[2-[1-[4-[3-(1,2-benzisothiazolyl)]]piperazinyl]-ethyl]-N-(2-pyridyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       15. A compound as claimed in claim 1 which is N-(2-(1-(4-(2-methoxyphenyl)piperazinyl))ethyl)-N-(1-piperidinylcarbonyl)-2-aminopyridine or a pharmaceutically acceptable salt thereof. 
     
     
       16. A compound as claimed in claim 1 which is N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-N-(pyridin-2-yl)-N'-cyclohexylthiourea or a pharmaceutically acceptable salt thereof. 
     
     
       17. A compound as claimed in claim 1 which is N-(2-(4-(2-hydroxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       18. A compound as claimed in claim 1 which is N-(2-(1-(4-(1-naphthyl))piperazinyl)ethyl)-N-(2-pyridyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       19. A compound as claimed in claim 1 which is N-(2-(1-(4-(2-methylphenyl))piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       20. A compound as claimed in claim 1 which is N-(2-(1-(4-(2-fluorophenyl))piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       21. A compound as claimed in claim 1 which is N-[2-[1-[4-(1-isoquinolinyl)]piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       22. A compound as claimed in claim 1 which is N-[2-[1-[4-[1-(7-methoxy)naphthyl]]piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       23. A compound as claimed in claim 1 which is N-(2-(1-(4-(2-methoxyphenyl)piperazinyl))ethyl)-N-(2-pyridyl)adamantane-1-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       24. A compound as claimed in claim 1 which is N-[2-[1-[4-[1-(2-methoxy)naphthyl]]piperazinyl]ethyl]-N-[2-pyridyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       25. A compound as claimed in claim 1 which is N-[2-[1-[4-[1-(5,6,7,8-tetrahydro)naphthyl]]-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       26. A compound as claimed in claim 1 which is (S)-N-(1-methyl-2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexane carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       27. A compound as claimed in claim 1 which is (R)-N-(1-methyl-2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexane carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       28. A compound as claimed in claim 1 which is N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-N-(2-pyridinyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       29. A compound as claimed in claim 1 which is N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-quinolinyl)cyclohexane carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       30. A compound as claimed in claim 1 which is (Rac)-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)propyl)-N-(2-pyridyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       31. A compound as claimed in claim 1 which is (S)-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)propyl)-N-(2-pyridyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       32. A compound as claimed in claim 1 which is (R)-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)propyl-N-(2-pyridyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       33. A compound as claimed in claim 1 which is N-(2-(4-phenyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)-cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       34. A compound as claimed in claim 1 which is N-(2-(4-(2-isopropylphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       35. A compound as claimed in claim 1 which is N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(4-pyridinyl)cyclohexane carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       36. A compound as claimed in claim 1 which is N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(3-pyridyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       37. A compound as claimed in claim 1 which is N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-N-(2-pyridinyl)cyclohex-1-enecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       38. A compound as claimed in claim 1 which is N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexane thiocarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
       39. A compound of the formula ##STR16## or a pharmaceutically acceptable acid addition salt thereof, wherein A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups; Z is oxygen or sulphur,   R is hydrogen or lower alkyl;   R 1  is aryl, tetrahydronaphthyl, heteroaxyl, wherein aryl, is phenyl or naphthyl each of which may be optionally substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, halogen, haloloweralkyl, nitro, nitrile aminocarbonyl, loweralkoxycarbonyl, amino, loweralkylamino, or di-loweralkylamino, and heteroaryl is a monocyclic aromatic heterocyclic ring having 5 ring members and having as heteroatoms one or two N atoms or one N atom and one O or S atom, or a monocyclic aromatic heterocyclic ring having 6 ring members and having as heteroatoms one or two N atoms, or a bicyclic aromatic heterocyclic ring system having one such 5 or 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring,   R 2  is a monocyclic aromatic heterocyclic ring having 6 ring members and having as heteroatoms one or two N atoms or a bicyclic aromatic heterocyclic ring system having one such 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, which may be optionally substituted as for aryl provided that, said bicyclic heterocyclic radical is connected to the amino nitrogen of formula I via such heterocyclic ring;   R 3  is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(loweralkyl), aryl, aryl(loweralkyl), a group of formula --NR 4  R 5 , or a group of formula OR 6 , in which R 4  is hydrogen, lower alkyl, aryl or aryl(loweralkyl) and R 5  is hydrogen, lower alkyl, --CO(loweralkyl), aryl, --COaryl, aryl(loweralkyl), cycloalkyl or cycloalkyl(loweralkyl), or R 4  and R 5  together with the nitrogen atom to which they are both attached represent azetidino pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino which may be optionally substituted by lower alkyl, aryl or aryl(loweralkyl), and   R 6  is lower alkyl cycloalkyl, cycloalkyl(loweralkyl), aryl or aryl(loweralkyl), wherein aryl is as defined for R 1  and cycloalkyl or cycloalkenyl is a mono-, bi-, tri-, or tetracyclic hydrocarbon group of 3 to 12 carbon atoms.   
     
     
       40. A compound of the formula ##STR17## or a pharmaceutically acceptable acid addition salt thereof, wherein A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups; Z is oxygen or sulphur;   R is hydrogen or lower alkyl;   R 1  is a bicyclic oxygen-containing aryl radical of the formula ##STR18## wherein the heterocyclic oxygen-containing ring has 5 to 7 ring members, said heterocyclic ring being non-aromatic and optionally having one further hetero ring member selected from --O--, --S--, --SO 2  or NR 7 ,   R 2  is a monocyclic aromatic heterocyclic ring having 6 ring members and having as heteroatoms one or two N atoms or a bicyclic aromatic heterocyclic ring system having one such 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, which may be optionally substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, halogen, haloloweralkyl, nitro, nitrite, aminocarbonyl, loweralkoxycarbonyl, amino, loweralkylamino, or di-loweralkylamino, provided that, said bicyclic heterocyclic radical is connected to the amino nitrogen of formula I via such heterocyclic ring;   R 3  is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(loweralkyl), aryl, aryl(loweralkyl), a group of formula --NR 4  R 5 , or a group of formula OR 6 , in which R 4  is hydrogen, lower alkyl, aryl or aryl(loweralkyl)   R 5  is hydrogen, lower alkyl, --CO(loweralkyl), aryl, --COaryl, aryl(loweralkyl), cycloalkyl or cycloalkyl(loweralkyl), or R 4  and R 5  together with the nitrogen atom to which they are both attached represent azetidino, pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino which may be optionally substituted by lower alkyl, aryl or aryl(loweralkyl),   R 6  is lower alkyl cycloalkyl, cycloalkyl(loweralkyl), aryl, or aryl(loweralkyl), wherein aryl is as defined for R 1  and cycloalkyl or cycloalkenyl is a mono-, bi-, tri-, or tetracyclic hydrocarbon group of3 to 12 carbon atoms;   R 7  is hydrogen or lower alkyl; and   R 8  and R 9  represent hydrogen or one or more substituents independently selected from lower alkyl, halogen, hydroxy, loweralkoxy, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkanoyloxy(loweralkyl), loweralkylcarbonyl, loweralkylcarbonyl(loweralkyl), amino, loweralkylamino or di-loweralkylamino.   
     
     
       41. A compound of the formula ##STR19## or a pharmaceutically acceptable acid addition salt thereof, wherein A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups; Z is oxygen or sulphur;   R is hydrogen or lower alkyl;   R 1  is a bicyclic oxygen-containing aryl radical of the formula ##STR20## R 2  is a monocyclic aromatic heterocyclic ring having 6 ring members and having as heteroatoms one or two N atoms or a bicyclic aromatic heterocyclic ring system having one such 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, which may be optionally substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, halogen, haloloweralkyl, nitro, nitrile, aminocarbonyl, loweralkoxycarbonyl, amino, loweralkylamino, or di-loweralkylamino, provided that, said bicyclic heterocyclic radical is connected to the amino nitrogen of formula I via such heterocyclic ring;   R 3  is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(loweralkyl), aryl, aryl(loweralkyl), a group of formula --NR 4  R 5 , or a group of formula OR 6 , in which R 4  is hydrogen, lower alkyl, aryl or aryl(loweralkyl) and R 5  is hydrogen, lower alkyl, --CO(loweralkyl), aryl, --COaryl, aryl(loweralkyl), cycloalkyl or cycloalkyl(loweralkyl), or R 4  and R 5  together with the nitrogen atom to which they are both attached represent azetidino, pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino which may be optionally substituted by lower alkyl, aryl or aryl(loweralkyl);   R 6  is lower alkyl, cycloalkyl, cycloalkyl(loweralkyl), aryl, or aryl(loweralkyl), wherein aryl is as defined for R 1  and cycloalkyl or cycloalkenyl is a mono-, bi-, tri-, or tetracyclic hydrocarbon group of 3 to 12 carbon atoms; and   R 8  and R 9  represent hydrogen or one or more substituents independently selected from lower alkyl, halogen, hydroxy, loweralkoxy, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkanoyloxy(loweralkyl), loweralkylcarbonyl, loweralkylcarbonyl(loweralkyl), amino, loweralkylamino or di-loweralkylamino.   
     
     
       42. A compound of the formula ##STR21## or a pharmaceutically acceptable acid addition salt thereof, wherein A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups, Z is oxygen or sulphur;   R is hydrogen or lower alkyl;   R 1  is a bicyclic oxygen-containing aryl radical selected from the group consisting of: ##STR22## R 2  is a monocyclic aromatic heterocyclic ring having 6 ring members and having as heteroatoms one or two N atoms or a bicyclic aromatic heterocyclic ring system having one such 6 membered monocyclic aromatic heterocyclic ring fused to a benzene ring, which may be optionally substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, halogen, haloloweralkyl, nitro, nitrile, aminocarbonyl, loweralkoxycarbonyl, amino, loweralkylamino, or di-loweralkylamino, provided that, said bicyclic heterocyclic radical is connected to the amino nitrogen of formula I via such heterocyclic ring;   R 3  is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(loweralkyl), aryl, aryl(loweralkyl), a group of formula --NR 4  R 5 , or a group of formula OR 6 , in which R 4  is hydrogen, lower alkyl, aryl or aryl(loweralkyl)   R 5  is hydrogen, lower alkyl, --CO(loweralkyl), aryl, --COaryl, aryl(loweralkyl), cycloalkyl or cycloalkyl(loweralkyl), or R 4  and R 5  together with the nitrogen atom to which they are both attached represent azetidino, pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino which may be optionally substituted by lower alkyl, aryl or aryl(loweralkyl),   R 6  is lower alkyl, cycloalkyl, cycloalkyl(loweralkyl), aryl, or aryl(loweralkyl), wherein aryl is as defined for R 1  and cycloalkyl or cycloalkenyl is a mono-, bi-, tri-, or tetracyclic hydrocarbon group of 3 to 12 carbon atoms; and   R 8  and R 9  represent hydrogen or one or more substituents independently selected from lower alkyl, halogen, hydroxy, loweralkoxy, hydroxyloweralkyl, loweralkoxyloweralkyl, loweralkanoyloxy(loweralkyl), loweralkylcarbonyl, loweralkylcarbonyl(loweralkyl), amino, loweralkylamino or di-loweralkylamino.   
     
     
       43. A method for treating anxiety in a mammal which comprises administering to said mammal an effective amount of a compound claimed in claim 1.